ABSTRACT Chronic pancreatitis provides proliferative advantage to oncogene-harboring pancreatic cells, shields transformed cells from anti-tumor factors, and stimulates the metastatic process. Accordingly, pancreatic inflammation emerges as an important factor in the development and progression of pancreatic ductal adenocarcinoma (PDA), which is a lethal disease with low survival rate. A better understanding of the anti- tumorigenic targets of pancreatic inflammation is critical for developing novel approaches to efficient therapies. In proposed here studies, we focus on the importance of type I interferons (IFN1) cytokines that act through IFNAR1 receptor to elicit a cell-autonomous tumor suppressive effects (e.g. cell senescence) in oncogene- harboring cells. Our preliminary results suggest that this pathway is inactivated in response to pancreatic inflammation-induced ubiquitination-dependent downregulation of IFNAR1 or through silencing of downstream effectors such as IFN1-inducible metabolic enzyme cholesterol 25-hydroxylase (CH25H). Our new exciting results include the observations that (i) IFNAR1 and CH25H are often lost in human PDA and mouse models of PDA, (ii) re-expression of CH25H in human and mouse PDA cells inhibits their proliferation/survival, and (iii) that genetic ablation of CH25H in mice stimulates PDA development. Based on these data we propose an overarching hypothesis that inactivation of the IFN1-IFNAR1-CH25H pathway promotes PDA development and progression. To test this hypothesis, we will characterize the IFN1-IFNAR1-CH25H pathway in human and mouse PDA and determine the effects of inactivation of IFNAR1 in vitro and in vivo on growth of pancreatic organoid cultures and development of PDA in mice. Conversely, cell-based and in vivo models deficient in IFNAR1 ubiquitination and downregulation will help to assess the importance of IFNAR1 loss in PDA development and progression. Furthermore, we propose to determine the tumor suppressive role of CH25H. We will use the organoid/cell-based models to delineate the mechanisms underlying the loss of CH25H induction by IFN1 in PDA cells and a novel conditional knockout model of CH25H to determine its importance in counteracting PDA development. We will also conduct preclinical studies using Liver X Receptor agonists (that act downstream of CH25H) against PDA in immunocompetent mice. Completion of these studies will determine the role of the IFN1-IFNAR1-CH25H pathway in PDA pathogenesis and delineate the mechanisms of inactivation of this pathway in PDA. We anticipate that future targeting of these mechanisms may be used for PDA treatment.